The research falls into three areas: 1) We will determine the responses of the serotonin (5-HT) synthesizing apparatus in rat brain to single and repeated administrations of drugs of abuse and various psychotherapeutic drugs to elucidate a) intraneuronal factors influencing the activity state of tryptophan hydroxylase (TPH), b) the dynamics of substrate availability at the enzyme site, which we have shown to be partially a function of the synaptosomal high affinity tryptophan uptake system, and c) regulatory adaptive changes in intraneuronal TPH. We will also examine the effects on the serotonergic system of the interactions of drugs of abuse with psychotherapeutic drugs. 2) We will examine the effects of hallucinogens and 5-HT and catecholamine (CA) agonists and antagonists (and some of their interactions) on behavioral variables reflecting animal responsitivity to stimuli and on microspectrofluorimetric measures of 5-HT ffuorescence in individual raphe neurons. These studies will incorporate selective lesions of the raphe nuclei prior to drug testing and the direct administration of selected drugs or transmitters into the raphe nuclei or forebrain structures such as hippocampus or striatum. 3) Addressing the functional role of reduced pterins in TPH and tyrosine hydroxylase (TYH) mediated elaboration of 5-HT and CA respectively, we will develop a profile of reduced pterin dynamics and disposition in brain relevant to the oxygenases in terms of regulatory function, biogenesis, steady-state plasticity, pharmacological intervention, in vitro mechanism/pathway studies, and potential pterin involvement in pathological states.